Traumatic brain injury (TBI) affects 1.7 million Americans each year. TBI is a significant cause of death and disease in the armed forces and the veteran population returning from wars in Iraq (Operation Iraqi Freedom; OIF) and Afghanistan (Operation Enduring Freedom; OEF). It has been estimated that that 10-20% of these returning veterans have suffered a TBI, and in many cases were not even diagnosed prior to discharge. Psychopathological symptoms associated with TBI include mood and anxiety disorders, post-traumatic stress disorder, suicidality, and diminished cognitive capacity with deficits in attention and memory. These symptoms can arise years after time of injury, leading to misdiagnosis and lack of proper care and treatment. With such staggering numbers of returning Veterans sustaining TBI and associated psychopathologies, understanding the molecular circuitry of TBI is critically important to the health and productivity of our Veteran population. To this end we propose to investigate epigenetic mechanisms' in blast-related TBI. Specifically, we will identify DNA methylation abnormalities induced in response to repeated blast exposure in both military personnel and animal model of blast-over-pressure. Modulation of gene expression mediated by epigenetic changes such as DNA methylation is one way the brain creates new homeostasis in response to experience, including blast exposure. We will utilize state-of-the-art sequencing and bioinformatics technologies to identify aberrant DNA methylation signatures associated with blast exposure. Such methylation abnormalities can confer gene expression abnormalities that can lead to development of psychiatric symptoms later in life. Combining data from animal model of repeated blast exposure together with data from human subjects from subpopulation of military Breacher personnel with exposure to repeated blast events, will allow us to determine whether the epigenetic alterations associated with blast exposure in animals are seen in the same genes or genetic pathways in human Breachers with immediate translational impact. This is a high-impact study that will not only further our understanding of the molecular mechanisms underlying blast-related TBI, but may also lead to identification of gene targets for future therapeutic intervention and substantially improve medical care of our veterans.